Development of 18F PET radiotracers for M2 microglia as diagnostics for multiplesclerosis pathogenesis
开发用于 M2 小胶质细胞的 18F PET 放射性示踪剂作为多发性硬化症发病机制的诊断
基本信息
- 批准号:10440539
- 负责人:
- 金额:$ 28.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ABCG2 geneAdultAffectAffinityAnimal ModelAnti-Inflammatory AgentsAutoradiographyBindingBinding SitesBiological MarkersBiological ProcessBrainC57BL/6 MouseCaucasiansCellsClinicalClinical ResearchClinical TrialsCuprizoneDevelopmentDiagnosticDiagnostic ReagentDigit structureDiseaseDisease OutcomeDoseEquipmentExhibitsFLT3 geneFailureFluoridesFluorineFreezingFutureGenesImageImmuneImmunohistochemistryIn VitroInflammatoryInflammatory ResponseInjuryKineticsLaboratoriesLeadLesionLigandsLinkMERTK geneMeasuresMediator of activation proteinMedical Care CostsMicrogliaModelingMonitorMultiple SclerosisMultiple Sclerosis LesionsMusNatureNerve DegenerationNervous system structureOutcomePathogenesisPathogenicityPatientsPenetrationPharmaceutical PreparationsPhasePhenotypePositron-Emission TomographyPredispositionPropertyProteinsRadioactiveRadiochemistryReceptor Protein-Tyrosine KinasesRodentRouteScanningSignal TransductionSliceSolubilityStratificationStructureTechniquesTestingTherapeutic InterventionTimeTissuesTracerTranslational ResearchVariantWorkblood-brain barrier permeabilizationcytokinedesigndiagnostic tooldifferential expressiondisabilityeconomic costimaging approachimprovedin vivokinase inhibitormacrophagemouse modelmultiple sclerosis patientnanomolarnervous system disordernext generationnon-invasive imagingnovelpatient stratificationradiochemicalradioligandradiotracerrepairedresponseresponse to injuryselective expressionsuccesstooltreatment responsetreatment strategyuptakeyoung adult
项目摘要
Project summary
Multiple sclerosis (MS) is the most common disabling neurodegenerative condition that affects young adults
around the world. Despite enormous efforts for treatment discovery, progressive disability, accompanied by very
significant adverse personal, medical and economic costs, remains very common. An important reason that
contributes to the unenviable track record of clinical trial failure for progressive MS is our inability to monitor in a
precise manner the status of MS at any given time. Although it has been established that the inflammatory cells
within the brain, known as microglia, are active in the progressive phase of the disease and most likely dictate
outcome, we remain unable to differentiate between MS-mediator and reparative microglia. Therefore, there is
a dire need to develop techniques that identify the subsets of microglia in order to stratify patients and offer them
adequate treatment.
Positron emission tomography (PET) has recently gained huge success as a non-invasive imaging approach to
accurately quantify biological processes within the brain. Thus far, PET imaging in MS patients has been
restricted to imaging a radioactive molecule, i.e. radioligand, that binds to a protein known as TSPO. However,
the recently observed variation of the TSPO gene, with some patients lacking binding of the radioligands, and
its inability to distinguish the activity of microglia limits its utility as a clinical and research tool. Building on our
previous results showing the selective upregulated expression of a protein by reparative microglia, we will
develop radioligands that bind to this protein and can be used for diagnostic purposes via PET. This highly
translational research plan will enable clinicians to classify MS in novel ways to guide therapeutic intervention in
MS patients in ways not previously possible.
The specific aims of this project are to (i) design and synthesize next-generation radioligands with optimized
binding and CNS penetration; (ii) generate radioactive versions of leading compounds; (iii) validate the
radioligands in MS mouse brain slices and assess them by PET in MS mouse models.
Outcome: This work will result in a diagnostic reagent that, using imaging equipment, will help clinicians monitor
the status of progressive MS in patients being treated in a manner that has never been possible before and
improve the success rates of new MS drugs being tested in clinical trials.
项目总结
多发性硬化症(MS)是影响年轻人的最常见的致残性神经退行性疾病
环游世界。尽管在治疗发现方面做出了巨大努力,但进行性残疾伴随着非常严重的
巨大的不利的个人、医疗和经济成本仍然非常普遍。一个重要的原因是
导致进展性多发性硬化症临床试验失败的不令人羡慕的记录的原因是我们无法在
以精确的方式显示MS在任何给定时间的状态。尽管已经证实炎性细胞
在大脑中,被称为小胶质细胞的细胞在疾病的进展阶段活跃,很可能决定了
结果,我们仍然不能区分MS介体和修复性小胶质细胞。因此,有
迫切需要开发识别小胶质细胞亚群的技术,以便对患者进行分层并为他们提供
适当的治疗。
正电子发射断层扫描(PET)作为一种非侵入性的成像方法,最近获得了巨大的成功
准确量化大脑内的生物过程。到目前为止,多发性硬化症患者的PET成像
仅限于对与一种称为TSPO的蛋白质结合的放射性分子,即放射性配体进行成像。然而,
最近观察到的TSPO基因变异,一些患者缺乏放射性配体的结合,以及
它无法区分小胶质细胞的活动,限制了其作为临床和研究工具的实用性。建立在我们的
先前的结果表明,修复性小胶质细胞选择性上调了蛋白质的表达,我们将
开发与这种蛋白质结合的放射性配体,并可通过PET用于诊断目的。如此之高
翻译研究计划将使临床医生能够以新的方式对多发性硬化症进行分类,以指导治疗干预
以前所未有的方式治疗多发性硬化症患者。
该项目的具体目标是(I)设计和合成具有优化的下一代放射性配体
结合和中枢神经系统渗透;(2)产生先导化合物的放射性版本;(3)验证
MS小鼠脑片中的放射性配基,并在MS小鼠模型中用PET进行评估。
结果:这项工作将产生一种诊断试剂,使用成像设备,将帮助临床医生监测
进展性多发性硬化症患者的状态正在以前所未有的方式接受治疗和
提高多发性硬化症新药临床试验成功率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Paul Anthony Stupple其他文献
Paul Anthony Stupple的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 28.82万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 28.82万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 28.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 28.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 28.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




